tbuckley/cabot-search huggingface dataset:
External Validation of a Prognostic Model of Overall Survival in Men With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer
Authors: Susan Halabi, Qian Yang, Akash Roy, Bin Luo, John C. Araujo, Christopher Logothetis, Cora N. Sternberg, Andrew J. Armstrong, Michael A. Carducci, Kim N. Chi, Johann S. de Bono, Daniel P. Petrylak, Karim Fizazi, Celestia S. Higano, Michael J. Morris, Dana E. Rathkopf, Fred Saad, Charles J. Ryan, Eric J. Small, William Kevin Kelly
Journal: Journal of Clinical Oncology (2023)

We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel. We sought to externally validate this model in a broader group of men with docetaxel-naïve mCRPC and in specific subgroups (White, Black, Asian patients, different age groups, and specific treatments) and to classify patients into validated two and three prognostic risk groupings on the basis of the model.
Reply to Y.-F. Zhao et al
Authors: Jie Sun, Yuntao Xie
Journal: Journal of Clinical Oncology (2023)

We thank Zhao et al 1 for their interest in and comments on our recent study that we built a prediction model (named BRCA-CRisk) for evaluating the individual risk of contralateral breast cancer (CBC) for BRCA carriers. 2BRCA carriers are unusually facing a hard question that they should retain their contralateral breast or a prophylactic mastectomy.Owing to our relatively large sample size of BRCA carriers that were derived from a large series of unselected breast cancer and a relatively long follow-up time (median follow-up, 7.0 years), we are able to build this model and we believe our model would aid the clinician and carriers for contralateral breast prophylactic surgery decision making.
5558131 GENETICS OF IRANIAN ALPHA THALASSEMIA PATIENTS; COMPREHENSIVE ORIGINAL STUDY
Authors: A. Khosravi, M. Karimzadeh, V. Takhviji
Journal: HemaSphere (2023)

Background: Alpha thalassemia is the most prevalent monogenic gene disorder in the world and especially in Mediterranean countries. In the current hematological phenotype of patients with different genotypes, and also the effect of missense mutations on the protein function and stability were evaluated in a large cohort study. Methods: One thousand five hundred and and sixty subjects were participated in the study and divided into two groups; 259 normal subjects and 1301 alpha thalassemia carriers. Genomic DNA was extracted and analyzed using ARMS PCR, Multiplex Gap and direct sequencing. The effects of single nucleotide change on the protein function and stability were predicted by free available databases of human polymorphisms. Results: Sixty-three different genotypes were seen in the patients. The more prevalent was heterozygote form of -α3.7 (41.4%) followed by -α3.7 homozygote(11.6%) and - -MED(3.8%). The significant differences were seen in mean hemoglobin level [F=20.5, p<0.001] between the Alpha globin genotypes, when adjusted for gender. Moreover, 28 different mutations were found in our study. A significant relationship was seen between ethnicity and the alpha globin mutation frequency X2 (df;8) = 38.36, p <0.0001). Conclusion: Different genotypes could be displayed as different phenotypes. The mutation frequency distributions in our region is different from other parts of Iran. Significant differences are seen in the spectrum of mutation frequency between various ethnicity. Finally, some missense mutations maybe did not considerably effect on the proteins and could be a neutral mutations. Keywords: Alpha Thalassemia, Genotype, Phenotype, Southwest of Iran References 1. Muncie Jr HL, Campbell J. Alpha and beta thalassemia. American family physician. 2009;80(4):339-44. 2. Vichinsky EP, MacKlin EA, Waye JS, Lorey F, Olivieri NF. Changes in the epidemiology of thalassemia in North America: a new minority disease. Pediatrics. 2005;116(6):e818-e25. 3. Harteveld CL, Higgs DR. α-thalassaemia. Orphanet journal of rare diseases. 2010;5(1):13.
Junior doctors’ strikes: it’s time to stop the walkouts and start negotiations
Authors: Fraz A Mir
Journal: BMJ (2023)

Junior doctors in the UK rarely go on strike.The current industrial action is on a scale not seen before. 1 The strikes starting today-scheduled for four days straight and immediately after the Easter bank holiday weekend-are designed to cause maximum disruption and inconvenience to an already overstretched health and social care system.The British Medical Association (BMA) has called the strikes as the last resort in highlighting the increasingly desperate state of the NHS, and the fact that it is under-resourced to the detriment of patient care and staff wellbeing.Junior doctors are also asking for full restoration for pay that has been eroded over 15 years of below inflation pay rises. 2 While it is right to blame the government for these myriad of failings, one wonders if we might have avoided this situation had we seen stronger leadership much sooner from the medical Royal Colleges, Health Education England, and even the General Medical Council (GMC) and the BMA itself, by advocating on behalf of junior doctors more vociferously and calling out the scale of the crisis in the NHS.
Crisaborole reverses dysregulation of the mild to moderate atopic dermatitis proteome toward nonlesional and normal skin
Authors: Madeline Kim, Ester Del Duca, Julia Cheng, Britta Carroll, Paola Facheris, Yeriel Estrada, Amy Cha, John Werth, Robert Bissonnette, Karl Nocka, Chuanbo Zang, Ana B. Pavel, Emma Guttman-Yassky
Journal: Journal of the American Academy of Dermatology (2023)
Outcomes of immunocompromised children hospitalized for Influenza, 2010-2021, the Canadian Immunization Monitoring Program Active (IMPACT)
Authors: Tilmann Schober, Shaun K. Morris, Julie A. Bettinger, Christina Bancej, Catherine Burton, Cheryl Foo, Scott A. Halperin, Taj Jadavji, Kescha Kazmi, Jacqueline Modler, Manish Sadarangani, Jesse Papenburg, Cheryl Foo, Natalie Bridger, Scott A. Halperin, Karina Top, Roseline Thibeault, Jesse Papenburg, Marc Lebel, Nicole Le Saux, Shaun K. Morris, Kescha Kazmi, Jared Bullard, Rupeena Purewal, Taj Jadavji, Catherine Burton, Julie A. Bettinger, Laura Sauvé, Manish Sadarangani
Journal: Clinical Microbiology and Infection (2023)
Risk of Cancer After Diagnosis of Cardiovascular Disease
Authors: Caitlin F. Bell, Xiudong Lei, Allen Haas, Richard A. Baylis, Hua Gao, Lingfeng Luo, Sharon H. Giordano, Mackenzie R. Wehner, Kevin T. Nead, Nicholas J. Leeper
Journal: JACC CardioOncology (2023)

Cardiovascular disease (CVD) and cancer share several risk factors. Although preclinical models show that various types of CVD can accelerate cancer progression, clinical studies have not determined the impact of atherosclerosis on cancer risk.
Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions
Authors: Tom G. Caniels, Max Medina-Ramírez, Jinsong Zhang, Anita Sarkar, Sonu Kumar, Alex LaBranche, Ronald Derking, Joel D. Allen, Jonne L. Snitselaar, Joan Capella-Pujol, Iván del Moral Sánchez, Anila Yasmeen, Marilyn Diaz, Yoann Aldon, Tom P.L. Bijl, Sravani Venkatayogi, Joshua S. Martin Beem, Amanda Newman, Chuancang Jiang, Wen-Hsin Lee, Maarten Pater, Judith A. Burger, Mariëlle J. van Breemen, Steven W. de Taeye, Kimmo Rantalainen, Celia LaBranche, Kevin O. Saunders, David Montefiori, Gabriel Ozorowski, Andrew B. Ward, Max Crispin, John P. Moore, Per Johan Klasse, Barton F. Haynes, Ian A. Wilson, Kevin Wiehe, Laurent Verkoczy, Rogier W. Sanders
Journal: Cell Reports Medicine (2023)

Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions.
A multi-omics atlas of the human retina at single-cell resolution
Authors: Qingnan Liang, Xuesen Cheng, Jun Wang, Leah Owen, Akbar Shakoor, John L. Lillvis, Charles Zhang, Michael Farkas, Ivana K. Kim, Yumei Li, Margaret DeAngelis, Rui Chen
Journal: Cell Genomics (2023)

Cell classes in the human retina are highly heterogeneous with their abundance varying by several orders of magnitude. Here, we generated and integrated a multi-omics single-cell atlas of the adult human retina, including more than 250,000 nuclei for single-nuclei RNA-seq and 137,000 nuclei for single-nuclei ATAC-seq. Cross-species comparison of the retina atlas among human, monkey, mice, and chicken revealed relatively conserved and non-conserved types. Interestingly, the overall cell heterogeneity in primate retina decreases compared with that of rodent and chicken retina. Through integrative analysis, we identified 35,000 distal
Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis
Authors: Gerard A Marchal, Niels Galjart, Vincent Portero, Carol Ann Remme
Journal: Cardiovascular Research (2023)

Abstract The cardiac sodium channel NaV1.5 is an essential modulator of cardiac excitability, with decreased NaV1.5 levels at the plasma membrane and consequent reduction in sodium current (INa) leading to potentially lethal cardiac arrhythmias. NaV1.5 is distributed in a specific pattern at the plasma membrane of cardiomyocytes, with localization at the crests, grooves, and T-tubules of the lateral membrane and particularly high levels at the intercalated disc region. NaV1.5 forms a large macromolecular complex with and is regulated by interacting proteins, some of which are specifically localized at either the lateral membrane or intercalated disc. One of the NaV1.5 trafficking routes is via microtubules (MTs), which are regulated by MT plus-end tracking proteins (+TIPs). In our search for mechanisms involved in targeted delivery of NaV1.5, we here provide an overview of previously demonstrated interactions between NaV1.5 interacting proteins and +TIPs, which potentially (in)directly impact on NaV1.5 trafficking. Strikingly, +TIPs interact extensively with several intercalated disc- and lateral membrane-specific NaV1.5 interacting proteins. Recent work indicates that this interplay of +TIPs and NaV1.5 interacting proteins mediates the targeted delivery of NaV1.5 at specific cardiomyocyte subcellular domains, while also being potentially relevant for the trafficking of other ion channels. These observations are especially relevant for diseases associated with loss of NaV1.5 specifically at the lateral membrane (such as Duchenne muscular dystrophy), or at the intercalated disc (for example, arrhythmogenic cardiomyopathy), and open up potential avenues for development of new anti-arrhythmic therapies.
N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer
Authors: Priska Auf der Maur, Marcel P. Trefny, Zora Baumann, Milica Vulin, Ana Luisa Correia, Maren Diepenbruck, Nicolas Kramer, Katrin Volkmann, Bogdan-Tiberius Preca, Pedro Ramos, Cedric Leroy, Tobias Eichlisberger, Katarzyna Buczak, Federica Zilli, Ryoko Okamoto, Roland Rad, Michael Rugaard Jensen, Christine Fritsch, Alfred Zippelius, Michael B. Stadler, Mohamed Bentires-Alj
Journal: Cell Reports Medicine (2023)

A genome-wide PiggyBac transposon-mediated screen and a resistance screen in a PIK3CAH1047R-mutated murine tumor model reveal NF1 loss in mammary tumors resistant to the phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor alpelisib. Depletion of NF1 in PIK3CAH1047R breast cancer cell lines and a patient-derived organoid model shows that NF1 loss reduces sensitivity to PI3Kα inhibition and correlates with enhanced glycolysis and lower levels of reactive oxygen species (ROS). Unexpectedly, the antioxidant N-acetylcysteine (NAC) sensitizes NF1 knockout cells to PI3Kα inhibition and reverts their glycolytic phenotype. Global phospho-proteomics indicates that combination with NAC enhances the inhibitory effect of alpelisib on mTOR signaling. In public datasets of human breast cancer, we find that NF1 is frequently mutated and that such mutations are enriched in metastases, an indication for which use of PI3Kα inhibitors has been approved. Our results raise the attractive possibility of combining PI3Kα inhibition with NAC supplementation, especially in patients with drug-resistant metastases associated with NF1 loss.
Engineered nanomaterials that exploit blood-brain barrier dysfunction for delivery to the brain
Authors: Jason R. Wu, Yazmin Hernandez, Katelyn F. Miyasaki, Ester J. Kwon
Journal: Advanced Drug Delivery Reviews (2023)

The blood–brain barrier (BBB) is a highly regulated physical and functional boundary that tightly controls the transport of materials between the blood and the brain. There is an increasing recognition that the BBB is dysfunctional in a wide range of neurological disorders; this dysfunction can be symptomatic of the disease but can also play a role in disease etiology. BBB dysfunction can be exploited for the delivery of therapeutic nanomaterials. For example, there can be a transient, physical disruption of the BBB in diseases such as brain injury and stroke, which allows temporary access of nanomaterials into the brain. Physical disruption of the BBB through external energy sources is now being clinically pursued to increase therapeutic delivery into the brain. In other diseases, the BBB takes on new properties that can be leveraged by delivery carriers. For instance, neuroinflammation induces the expression of receptors on the BBB that can be targeted by ligand-modified nanomaterials, and the endogenous homing of immune cells into the diseased brain can be hijacked for the delivery of nanomaterials. Lastly, BBB transport pathways can be altered to increase nanomaterial transport. In this review, we will describe changes that can occur in the BBB in disease, and how these changes have been exploited by engineered nanomaterials for increased transport into the brain.
Epigenetic programing of cancer stemness by transcription factors-non-coding RNAs interactions
Authors: Reem Khaled M.E. Alsayed, Khalid Sultan A.M. Sheikhan, Majid Ali Alam, Jorg Buddenkotte, Martin Steinhoff, Shahab Uddin, Aamir Ahmad
Journal: Seminars in Cancer Biology (2023)

Cancer 'stemness' is fundamental to cancer existence. It defines the ability of cancer cells to indefinitely perpetuate as well as differentiate. Cancer stem cell populations within a growing tumor also help evade the inhibitory effects of chemo- as well as radiation-therapies, in addition to playing an important role in cancer metastases. NF-κB and STAT-3 are representative transcription factors (TFs) that have long been associated with cancer stemness, thus presenting as attractive targets for cancer therapy. The growing interest in non-coding RNAs (ncRNAs) in the recent years has provided further insight into the mechanisms by which TFs influence cancer stem cell characteristics. There is evidence for a direct regulation of TFs by ncRNAs, such as, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) as well as circular RNAs (circRNAs), and vice versa. Additionally, the TF-ncRNAs regulations are often indirect, involving ncRNA-target genes or the sponging of other ncRNA species by individual ncRNAs. The information is rapidly evolving and this review provides a comprehensive review of TF-ncRNAs interactions with implications on cancer stemness and in response to therapies. Such knowledge will help uncover the many levels of tight regulations that control cancer stemness, providing novel opportunities and targets for therapy in the process.
5613423 TREATMENT OF ERYTHROID PRECURSOR CELLS FROM β-THALASSEMIC PATIENTS WITH ISOXAZOLE DERIVATIVES: POTENT INDUCTION OF FETAL HEMOGLOBIN
Authors: C.Z. Cristina Zuccato, L.C.C. Lucia Carmela Cosenza, G.S. Gianni Sacchetti, R.R. Riccardo Rondanin, D.S. Daniele Simoni, M.P. Marco Prosdocimi, M.L.P. Lipucci di Paola, A.F. Alessia Finotti, R.G. Roberto Gambari, I.L. Ilaria Lampronti
Journal: HemaSphere (2023)

Background: Increased production of fetal hemoglobin (HbF) can be beneficial for β-thalassemia patients and several clinical trials in β-thalassemia and/or sickle-cell disease (SCD) are ongoing using HbF inducers, such as NCT01245179 (based on the HDAC inhibitor Panobinostat), NCT00790127 (based on 2,2-dimethylbutyrate, HQK-1001) and NCT03877809 (based on the mTOR inhibitor sirolimus). Methods: In this context, new molecules able to induce HbF are needed. In this communication, we have studied in deep a new class of promising HbF inducers characterized by an isoxazole chemical skeleton. These derivatives are 3,4-isoxazolediamide compounds recently synthesized in our laboratories. The original structures of two natural molecules, geldanamycin and radicicol, known to be natural Hsp (Heat Shot Protein) inhibitors, were modified to lead to a novel class of synthetic compounds, containing the isoxazole nucleus, and displaying potent and selective inhibition of Hsp90. Here we used erythroid precursors cells (ErPCs) isolated from β-thalassemic patients and treated with appropriate concentrations of 8 isoxazole derivatives previously demonstrated to be able to induce erythroid differentiation of K562 cells. Results: We demonstrated the high efficacy of the analyzed isoxazoles in inducing HbF. Some derivatives demonstrated an activity even higher than other HbF inducers used as positive controls, such as Hydroxyurea (HU) or Sirolimus. Most of the isoxazole derivatives displayed high effects in decreasing the excess of free α-globin chains in treated ErPCs. All the compounds were assayed for genotoxicity through the Ames test, employing the histidine-requiring Salmonella typhimurium mutant TA 97A, TA98, TA100 and TA1535 strains that allow to check frameshift mutation and base-pair substitution, with and without metabolic activation induced by S9 Mix. These assays excluded any drawbacks related to genotoxicity. Summary - Conclusion: We may therefore conclude that these novel isoxazoles could be proposed for clinical studies for possible therapeutic application for the treatment of β-thalassemia. These compounds have been recently patented as potential therapeutic agents for β-thalassemia (US Patent 11077116). Acknowledgements This study was sustained by the Wellcome Trust (innovator award 208872/Z/17/Z), by AIFA (AIFA-2016-02364887) and by the UE THALAMOSS Project (Thalassemia Modular Stratification System for Personalized Therapy of Βeta-Thalassemia; no. 306201-FP7-HEALTH-2012-INNOVATION-1). We thank A.L.T. (Associazione per la lotta alla Talassemia) “Rino Vullo” - Ferrara, and A.V.L.T. (Associazione Veneta per la Lotta alla Talassemia) “Elio Zago” - APS – Rovigo.
5613514 PAVING THE WAY FOR GENETIC MEDICINE IN SUB-SAHARAN AFRICA: A REPORT ON THE FIRST GENETIC COUNSELLING PROGRAM IN THE REGION
Authors: J.A. Osae-Larbi, S.F. Ofori-Acquah, K.A. Anie, A. Osei-Tutu
Journal: HemaSphere (2023)

Genetic disorders, chiefly sickle cell disease (SCD), pose a significant public health and developmental challenge in the sub-Saharan African region and genetic counsellors have a unique role to play in addressing this critical challenge in the region. Paradoxically, as at 2021, there were no postgraduate training programmes in human genetics in West Africa. Thus, whereas there were thousands of registered Genetic Counsellors in North America, there were about 25 in Africa, all in South Africa. In January 2022, the West African Genetic Medicine Centre (WAGMC) of the University of Ghana (UG), West Africa, inaugurated the first genetic counselling program in the sub-region. The two-year full-time accredited program aims to provide cutting edge training in the science of genetics while fostering a strong foundation in counselling. Graduates from the 2-year program further undertake one-year internship to be licensed as genetic counsellors by the Ghana Psychology Council, which is the body responsible for ensuring ethical genetic counselling practice in Ghana. In Ghana, where about 14,000 babies are born with SCD every year and the incidence of other genetic disorders keep rising, it is the goal of current genetic and genomic initiatives in the region to better understand these conditions and help drive preventive and precision medicine. This requires the contributions of genetic counsellors. Therefore, the new MSc. Program in Genetic Counselling holds vast opportunities for the first cohort and all prospective students on the program, despite the anticipated challenges. These include limited genetic testing facilities as well as resources for integrating genetic counsellors into the clinical and public health systems of Ghana and other countries in the sub-region. References 1. Cikomola et al, Acta Clin Behg 2018; 1:6 2. Piel et al, PLoS Med 2013;10:7 3. Osafo et al, Kidney Int 2016; 90:2-5 4. Ormond et al, Am J Med Genet C Semin Med Genet 2018; 178:98-107
Exacerbation Risk and Mortality in Global Initiative for Chronic Obstructive Lung Disease Group A and B Patients with and without Exacerbation History
Authors: Lowie E. G. W. Vanfleteren, Anne Lindberg, Caddie Zhou, Fredrik Nyberg, Caroline Stridsman
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Risk stratification of patients according to chronic obstructive pulmonary disease severity is clinically important and forms the basis of therapeutic recommendations. No studies have examined the association for Global Initiative for Chronic Obstructive Lung Disease (GOLD) group A and group B patients with (A1 and B1, respectively) and without (A0 and B0, respectively) an exacerbation in the past year with future exacerbations, hospitalizations, and mortality in perspective with the new GOLD ABE classification. Objectives: The aim was to examine the association between GOLD A0, A1, B0, B1, and E patients and future exacerbations, respiratory and cardiovascular hospitalizations, and mortality. Methods: In this nationwide cohort study, we identified patients with a diagnosis of chronic obstructive pulmonary disease, aged ⩾30 years, and registered in the Swedish National Airway Register between January 2017 and August 2020. Patients were stratified in GOLD groups A0, A1, B0, B1, and E and were followed until January 2021 for exacerbations, hospitalizations, and mortality in national registries. Measurements and Main Results: The 45,350 eligible patients included 25% A0, 4% A1, 44% B0, 10% B1, and 17% E. Moderate exacerbations, all-cause and respiratory hospitalizations, and all-cause and respiratory mortality increased by GOLD group A0-A1-B0-B1-E, except for moderate exacerbations, which were higher in A1 than in B0. Group B1 had a substantially higher hazard ratio for future exacerbation (2.56; 95% confidence interval [95% CI] 2.40-2.74), all-cause hospitalization (1.28; 1.21-1.35), and respiratory hospitalization (1.44; 1.27-1.62), but not all-cause (1.04; 0.91-1.18) or respiratory (1.13; 0.79-1.64) mortality than group B0. The exacerbation rate for group B1 was 0.6 events per patient-year versus 0.2 for group B0 (rate ratio, 2.55; 95% CI, 2.36-2.76). Results were similar for group A1 versus group A0. Conclusions: Stratification of GOLD A and B patients with one or no exacerbation in the past year provides valuable information on future risk, which should influence treatment recommendations for preventive strategies.